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NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val) AND not provided

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 17, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000223824.8

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)]

NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)

Gene:
KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.5
Genomic location:
Preferred name:
NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)
HGVS:
  • NC_000011.10:g.2583544C>T
  • NG_008935.1:g.143554C>T
  • NM_000218.3:c.1031C>TMANE SELECT
  • NM_001406836.1:c.1031C>T
  • NM_001406837.1:c.761C>T
  • NM_001406838.1:c.587C>T
  • NM_181798.2:c.650C>T
  • NP_000209.2:p.Ala344Val
  • NP_000209.2:p.Ala344Val
  • NP_001393765.1:p.Ala344Val
  • NP_001393766.1:p.Ala254Val
  • NP_001393767.1:p.Ala196Val
  • NP_861463.1:p.Ala217Val
  • NP_861463.1:p.Ala217Val
  • LRG_287t1:c.1031C>T
  • LRG_287t2:c.650C>T
  • LRG_287:g.143554C>T
  • LRG_287p1:p.Ala344Val
  • LRG_287p2:p.Ala217Val
  • NC_000011.9:g.2604774C>T
  • NM_000218.2:c.1031C>T
  • NM_181798.1:c.650C>T
  • NR_040711.2:n.924C>T
  • P51787:p.Ala344Val
Protein change:
A196V
Links:
UniProtKB: P51787#VAR_001541; dbSNP: rs199472763
NCBI 1000 Genomes Browser:
rs199472763
Molecular consequence:
  • NM_000218.3:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406838.1:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.650C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
10

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000234461GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Pathogenic
(May 17, 2022) 		germlineclinical testing

Citation Link,

SCV000280136Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Pathogenic
(Jul 16, 2015) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided10not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000234461.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on KCNQ1 channel function (Siebrands et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15840476, 19716085, 29444113, 16931984, 12388934, 22095730, 15466642, 9386136, 17470695, 28944242, 9570196, 29033053, 31589614, 28438721, 31737537, 34505893)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280136.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala344Val This variant has been published in multiple cases of long QT syndrome. Donger et al (1997) reported the variant in 6 members of one family with long QT syndrome. It’s not clear how many of those family members actually had clinically diagnosed long QT. The average QTc among those family members was 471 ms (+/-32) and 2 of the 6 carriers were symptomatic (syncope). Tester et al (2005) reported the variant in three cases of long QT syndrome referred to Mayo Clinic’s Sudden Death Genomics Laboratory for genetic testing. In a study on genotype-phenotype correlations, Moss et al (2007) reported 17 individuals with this variant, though it is not clear if they all had a clinical diagnosis of long QT syndrome. Another missense variant at the same codon has been reported in someone with long QT syndrome: p.Ala344Glu (Tester et al 2005). Tester et al (2005) did not see the variant in more than 750 control individuals of varied ancestry. Donger et al (1997) did not observe the variant in 100 control subjects, for a total of 1050 control individuals. As of Oct 2013: It is not present in the NHLBI Exome Sequencing Project dataset of approximately 6500 individuals of Caucasian and African American ancestry. Based on these data it is very likely that this variant causes long QT syndrome and that the risk of cardiac events is increased because of the location of this variant. It affects a highly conserved amino acid residue in an important functional domain of the protein: the S6 transmembrane domain. Of note, variants like this one that are located in the transmembrane region of the channel are correlated with a higher risk of cardiac events (hazard ratio 2.06), independent of traditional clinical risk factors such as age, gender, and QTc length (Moss et al 2007).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided10not providednot providednot provided

Last Updated: Sep 29, 2024